Hepatitis D virus or hepatitis delta virus (HDV) is a human pathogen. Indeed HDV infection is highly endemic to several African countries, the Amazonian region, and the Middle East, while its prevalence is low in industrialized countries, except in the Mediterranean. However, the virus is defective and depends on obligatory helper functions provided by the hepatitis B virus (HBV) for transmission; indeed, HDV requires a simultaneous infection with HBV (co-infection) or superimposition on a pre-existing HBV infection (superinfection) to become infectious and thrive. In particular, HDV requires the HBV viral envelope containing the surface antigen of hepatitis B.
HDV is unique in human virology; it has a circular RNA genome of about 1,700 bases (see, e.g., Genbank Accession No. M21012.1 (GI:329989)) and is therefore the smallest infectious agent in man, and is similar to viroids and satellite RNAs of plants. HDV replicates by a rolling circle mechanism unknown to animal cells, possesses a self-cleaving ribozyme and is transcribed by host RNA polymerases that normally accept only DNA templates (Ciancio and Rizzetto, Nat. Rev. 11:68-71, 2014).
HDV is a circular, single stranded RNA virus that ranges from 1,672 (strain dFr45, Genbank accession number AX741144) to 1,697 nucleotides (dFr47, GenBank accession number AX741149). A unique open reading frame encodes the small and large hepatitis delta (sHD and lHD, respectively) antigens by way of an editing step in the hepatocyte nucleus.
The genetic diversity of HDV is related to the geographic origin of the isolates and there are at least eight genotypes that are referred to as HDV-1 through HDV-8. Apart from HDV-1, which is ubiquitous, HDV-2 (previously labeled HDV-IIa) is found in Japan, Taiwan, and Yakoutia, Russia; HDV-4 (previously labeled HDV-IIb) in Taiwan and Japan; HDV-3 which causes epidemics of severe and fulminant hepatitis in the Amazonian region (9); and HDV-5, HDV-6, HDV-7, and HDV-8 in Africa (LeGal et al., Emerg. Infect. Dis. 12:1447-1450, 2006).
Worldwide more than 400 million people are chronically infected with HBV. Furthermore, at the end of the 1980s, at least 5% of hepatitis B surface antigen (HBsAg) carriers throughout the globe (˜15 million individuals) were estimated to also be infected with HDV. Subjects infected with HBV are at increased risk of developing serious liver disease, such as chronic hepatitis, cirrhosis, liver failure and hepatocellular carcinoma (HCC) resulting in an estimated 600,000 deaths each year, HDV infection in such subjects (either co-infection or superinfection) can lead to severe acute and chronic forms of liver disease in association with HBV. In fact, both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone. These complications include resistance to treatment with standard therapies and a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased chance of developing liver cancer in chronic infections. In combination with hepatitis B virus, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%.
Accordingly, there is a need in the art for alternative therapies and combination therapies for subjects infected with HDV and/or having an HDV-associated disease.